The 27-year-old batsman, in only his 10th game, played the anchor role with a knock of 131 not out as his side closed on 263 for three in reply to their opponents’ 249 all out.
He is just seven runs short of surpassing Pakistan’s highest individual score against South Africa set by Azhar Mahmood.
Manzoor and debutant Shan Masood (75) shared their country’s first century opening stand since January 2012 as they piled on 135 either side of lunch.
Mansoor’s departure saw Pakistan suffer a minor stumble as they slipped from 135 without loss to 178 for three but Manzoor remained steadfast and with Misbah-ul-Haq added a further 85 up to stumps.
Having brought up his 50 off 96 balls before tea Manzoor continued his progress to three figures, bringing up his landmark off 198 balls hitting 11 fours.
By that time he had already seen three wickets fall at the other end with off-spinner Jean-Paul Duminy first pinning Masood lbw bowling around the wicket.
Masood made a futile attempt to review the decision but took so long to make the request too much time had elapsed for it to be brought into play and in any case television replays showed the ball would have hit leg stump having pitched on middle and off.
Brief scores: Pakistan 263-3 (Khurram Manzoor 131*, Shan Masood 75, Morne Morkel 1-23) vs South Africa 249 (Hashim Amla 118; JP Duminy 57; Mohammad Irfan 3-44, Zulfiqar Babar 3-89)